Silencing of E2F3 suppresses tumor growth of Her2+ breast cancer cells by restricting mitosis
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Miyoung Lee1, Gabriela Oprea-Ilies2, Harold I. Saavedra1,3
1Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
2Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Grady Memorial Hospital, Atlanta, GA 30303, USA
3Department of Basic Sciences, Pharmacology Division, Ponce Health Sciences University, Ponce Research Institute, Ponce, P.R. 00716-2348, USA
Harold I. Saavedra, e-mail: firstname.lastname@example.org
Keywords: E2F3, Her2+ breast cancer, centrosome amplification, mitosis, xenograft mammary tumor model
Received: February 02, 2015 Accepted: October 16, 2015 Published: October 26, 2015
The E2F transcriptional activators E2F1, E2F2 and E2F3a regulate many important cellular processes, including DNA replication, apoptosis and centrosome duplication. Previously, we demonstrated that silencing E2F1 or E2F3 suppresses centrosome amplification (CA) and chromosome instability (CIN) in Her2+ breast cancer cells without markedly altering proliferation. However, it is unknown whether and how silencing a single E2F activator, E2F3, affects malignancy of human breast cancer cells. Thus, we injected HCC1954 Her2+ breast cancer cells silenced for E2F3 into mammary fat pads of immunodeficient mice and demonstrated that loss of E2F3 retards tumor growth. Surprisingly, silencing of E2F3 led to significant reductions in mitotic indices relative to vector controls, while the percentage of cells undergoing S phase were not affected. Nek2 is a mitotic kinase commonly upregulated in breast cancers and a critical regulator of Cdk4- or E2F-mediated CA. In this report, we found that Nek2 overexpression rescued back the CA caused by silencing of shE2F3. However, the effects of Nek2 overexpression in affecting tumor growth rates of shE2F3 and shE2F3; GFP cells were inconclusive. Taken together, our results indicate that E2F3 silencing decreases mammary tumor growth by reducing percentage of cells undergoing mitosis.
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